Estimation of interdomain flexibility of N-terminus of factor H using residual dipolar couplings

Characterization of segmental flexibility is needed to understand the biological mechanisms of the very large category of functionally diverse proteins, exemplified by the regulators of complement activation, that consist of numerous compact modules or domains linked by short, potentially flexible, sequences of amino acid residues. The use of NMR-derived residual dipolar couplings (RDCs), in magnetically aligned media, to evaluate interdomain motion is established but only for two-domain proteins. We focused on the three N-terminal domains (called CCPs or SCRs) of the important complement regulator, human factor H (i.e. FH1-3). These domains cooperate to facilitate cleavage of the key complement activation-specific protein fragment, C3b, forming iC3b that no longer participates in the complement cascade. We refined a three-dimensional solution structure of recombinant FH1-3 based on nuclear Overhauser effects and RDCs. We then employed a rudimentary series of RDC datasets, collected in media containing magnetically aligned bicelles (disk-like particles formed from phospholipids) under three different conditions, to estimate interdomain motions. This circumvents a requirement of previous approaches for technically difficult collection of five independent RDC datasets. More than 80% of conformers of this predominantly extended three-domain molecule exhibit flexions of < 40 °. Such segmental flexibility (together with the local dynamics of the hypervariable loop within domain 3), could facilitate recognition of C3b via initial anchoring and eventual reorganization of modules to the conformation captured in the previously solved crystal structure of a C3b:FH1-4 complex

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals

Analyzing collaborative learning processes automatically

In this article we describe the emerging area of text classification research focused on the problem of collaborative learning process analysis both from a broad perspective and more specifically in terms of a publicly available tool set called TagHelper tools. Analyzing the variety of pedagogically valuable facets of learners’ interactions is a time consuming and effortful process. Improving automated analyses of such highly valued processes of collaborative learning by adapting and applying recent text classification technologies would make it a less arduous task to obtain insights from corpus data. This endeavor also holds the potential for enabling substantially improved on-line instruction both by providing teachers and facilitators with reports about the groups they are moderating and by triggering context sensitive collaborative learning support on an as-needed basis. In this article, we report on an interdisciplinary research project, which has been investigating the effectiveness of applying text classification technology to a large CSCL corpus that has been analyzed by human coders using a theory-based multidimensional coding scheme. We report promising results and include an in-depth discussion of important issues such as reliability, validity, and efficiency that should be considered when deciding on the appropriateness of adopting a new technology such as TagHelper tools. One major technical contribution of this work is a demonstration that an important piece of the work towards making text classification technology effective for this purpose is designing and building linguistic pattern detectors, otherwise known as features, that can be extracted reliably from texts and that have high predictive power for the categories of discourse actions that the CSCL community is interested in

The politics of the digital single market:Culture vs. competition vs. copyright

This paper examines the implications for European music culture of the European Union’s Digital Single Market strategy. It focuses on the regulatory framework being created for the management of copyright policy, and in particular the role played by Collective Management Organisations (or Collecting Societies). One of the many new opportunities created by digitalization has been the music streaming services. These depend on consumers being able to access music wherever they are, but such a system runs counter to the management of rights on a national basis and through collecting organisations who act as monopolies within their own territories. The result has been ‘geo-blocking’. The EU has attempted to resolve this problem in a variety of ways, most recently in a Directive designed to reform the CMOs. In this paper, we document these various efforts, showing them to be motivated by a deep-seated and persisting belief in the capacity of ‘competition’ to resolve problems that, we argue, actually lie elsewhere - in copyright policy itself. The result is that the EU’s intervention fails to address its core concern and threatens the diversity of European music culture by rewarding those who are already commercially successful

Conversation acts in task-oriented spoken dialogue

A linguistic form\u27s compositional, timeless meaning can be surrounded or even contradicted by various social, aesthetic, or analogistic companion meanings. This paper addresses a series of problems in the structure of spoken language discourse, including turn-taking and grounding. It views these processes as composed of fine-grained actions, which resemble speech acts both in resulting from a computational mechanism of planning and in having a rich relationship to the specific linguistic features which serve to indicate their presence. The resulting notion of Conversation Acts is more general than speech act theory, encompassing not only the traditional speech acts but turn-taking, grounding, and higher-level argumentation acts as well. Furthermore, the traditional speech acts in this scheme become fully joint actions, whose successful performance requires full listener participation. This paper presents a detailed analysis of spoken language dialogue. It shows the role of each class of conversation acts in discourse structure, and discusses how members of each class can be recognized in conversation. Conversation acts, it will be seen, better account for the success of conversation than speech act theory alone

Antineoplastic activity of idazoxan hydrochloride

Idazoxan hydrochloride (IDA) is a 241 molecular weight imidazoline and adrenoreceptor ligand. It binds to mitochondrial membranes and promotes apoptosis of pancreatic beta cells. Since IDA has not been tested against tumor cells, the purpose of our study was to determine if IDA has antineoplastic activity. We used the conversion of a soluble tetrazolium salt to an insoluble formazan precipitate and differential staining cytotoxicity assays to determine if IDA was cytotoxic to cell lines of murine lung cancer and human prostate cancer, as well as to a variety of fresh human tumor samples. We used flow cytometry to analyze cell death and calreticulin expression. IDA is cytotoxic to both cell lines and against aliquots of specimens of breast, gastric, lung, ovarian and prostate cancers as well as non-Hodgkin’s lymphoma. It produces apoptotic cell death and promotes calreticulin expression, suggesting that IDA might be immunomodulatory in vivo. We anticipate that IDA will be clinically useful in cancer treatment

Improving automobile insurance ratemaking using telematics: incorporating mileage and driver behaviour data

We show how data collected from a GPS device can be incorporated in motor insurance ratemaking . The calculation of premium rates based upon driver behaviour represents an opportunity for the insurance sector . Our approach is based on count data regression models for frequency, where exposure is driven by the distance travelled and additional paramete rs that capture characteristics of automobile usage and which may affect claiming behaviour . We propose implement ing a classical frequency model that is updated with telemetrics information. We illustrate the method using real data from usage - based insurance policies. Results show that not only the distance travelled by the driver, but also driver habits, significantly influence the expected number of accidents and, hence, the cost of insurance coverage . This paper provides a methodology including a transition pricing transferring knowledge and experience that the company already had before the telematics data arrived to the new world including telematics information incorporated in motor insurance ratemaking . The calculation of premium rates based upon driver behaviour represents an opportunity for the insurance sector. Our approach is based on count data regression models for frequency, where exposure is driven by the distance travelled and additional parameters that capture characteristics of automobile usage and which may affect claiming behaviour. We propose implementing a classical frequency model that is updated with telemetrics information. We illustrate the method using real data from usage - based insurance policies. Results show that not only the distance travelled by the driver, but also driver habits, significantly influence the expected number of accidents and, hence, the cost of insurance coverage . This paper provides a methodology including a transition pricing transferring knowledge and experience that the company already had before the telematics data arrived to the new world including telematics information